Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 in Antidiabetic Therapy

Wang, Minghan

doi:10.1007/978-3-642-17214-4_6

Cited by 22 publications

(24 citation statements)

References 101 publications

(127 reference statements)

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“…Cortisol regulates energy metabolism through gluconeogenesis, but also affects processes such as infl ammation (19,20). Various cortisol-regulated physiological processes depend on glucocorticoid receptor (GR), which is activated upon cortisol binding (20,21). On the pre-receptor level, cortisol action is additionally regulated by the intracellular enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) (20,22,23) that comes in two isoforms: type 1 (11β-HSD1) and type 2 (11β-HSD2).…”

Section: Endocrine Factors and Metsmentioning

confidence: 99%

“…Type 1 catalyses the conversion of the inactive form cortisone into active cortisol, while type 2 converts active cortisol into its inactive form cortisone to lower the levels of active glucocorticoid and to inhibit cortisol activity (22,24). Therefore, the level of cortisol in a particular tissue depends on blood cortisol levels produced by the adrenal gland and on tissue activity of 11β-HSD1 and density of GR ( Figure 1) (20,21).…”

Section: Endocrine Factors and Metsmentioning

confidence: 99%

“…One promising specific-target approach is the inhibition of the 11β-HSD1 enzyme in order to normalise cortisol (21,22). Studies on animals and humans have shown that pharmacological inhibition of 11β-HSD1 activity has favourable metabolic (reduction of glucose level, insulin resistance, and dyslipidaemia) and anti-infl ammatory effects (22,23,72).…”

Section: Treatment Of Metsmentioning

confidence: 99%

“…75). This fi nding is important since 11β-HSD1 could be a valid therapeutic target not only for obesity and MetS, but also for other comorbidities, such as type 2 diabetes (21,72).…”

Section: Treatment Of Metsmentioning

confidence: 99%

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Endocrine, Lifestyle, and Genetic Factors in the Development of Metabolic Syndrome

Slanovic-Kuzmanović

Kos

Domijan

2013

Archives of Industrial Hygiene and Toxicology

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Metabolic syndrome (MetS) is a chronic, multi-component disease characterised by central obesity, hyperglycaemia, dyslipidaemia, and hypertension. Since MetS leads to type 2 diabetes, cardiovascular disease, development of certain cancers, and eventually to premature death, it is not surprising that it draws the attention of scientists around the world. The aetiopathology of MetS is complex and still not fully understood. This review focuses on the role of endocrine factors such as cortisol and insulin in the development of MetS. It also takes a look at some of the contributing lifestyle and genetic factors as well as at the current knowledge about its treatment. Slanovic-Kuzmanović Z, et al. ENDOCRINE, LIFESTYLE, AND GENETIC RISK FACTORS FOR METS Arh Hig Rada Toksikol 2013;64:581-591 Metabolic syndrome (MetS) is a modern disease characterised by the clustering of abnormalities such as central obesity, high levels of fasting glucose and triglyceride, low levels of high-density lipoprotein (HDL), and hypertension (1, 2). The prevalence of MetS has been increasing over the past two decades (1), and recent studies (3-5) suggest that it has reached 25 % among the adults worldwide. Reports vary from 21.9 % in men and 16.8 % in women in north-eastern Italy, and 24.6 % in alcohol-dependent male patients in north India to 31.25 % in rural women from Bangladesh. A small study on salt intake with 92 participants in Croatia reports the prevalence of 31.5 % (6). Among obese adolescents and pubertal children, the prevalence of MetS could be around 15 %, judging by the reports of 14 % in Danish obese adolescents (7) and of 9.7 % to 41.2 % in obese pubertal children and 8.3 % to 34.2 % in obese prepubertal children in Spain (8). KEY WORDS: cardiovascular diseases, circadian rhythm, cortisol, hyperglycaemia, hypertension, insulin, MetS, type 2 diabetes

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Section: Endocrine Factors and Metsmentioning

confidence: 99%

Section: Endocrine Factors and Metsmentioning

confidence: 99%

Section: Treatment Of Metsmentioning

confidence: 99%

“…75). This fi nding is important since 11β-HSD1 could be a valid therapeutic target not only for obesity and MetS, but also for other comorbidities, such as type 2 diabetes (21,72).…”

Section: Treatment Of Metsmentioning

confidence: 99%

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Endocrine, Lifestyle, and Genetic Factors in the Development of Metabolic Syndrome

Slanovic-Kuzmanović

Kos

Domijan

2013

Archives of Industrial Hygiene and Toxicology

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“…1 GR signaling depends not only on the circulating cortisol levels but also on the intracellular production of cortisol through reduction of cortisone, the inactive glucocorticoid. The enzymes catalyzing the conversion between cortisone and cortisol are 11β-hydroxysteroid dehydrogenases (11β-HSDs).…”

mentioning

confidence: 99%

Discovery of 2-Alkyl-1-arylsulfonylprolinamides as 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Liu

Xia

et al. 2012

ACS Med. Chem. Lett.

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On the basis of scaffold hopping, a novel series of 2-alkyl-1-arylsulfonylprolinamides was discovered as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) inhibitors. A representative compound 4ek, obtained through SAR and structure optimization studies, demonstrates excellent in vitro potency against 11β-HSD-1 and dose-dependent in vivo inhibition of 11β-HSD-1 in a prednisone/prednisolone transformation biomarker study in mice.KEYWORDS: metabolic syndrome, enzyme inhibitor, 11β-hydroxysteroid dehydrogenase type 1, sulfonamide, 2-alkylproline, prolinamide G lucocorticoid receptor (GR) signaling plays a significant role in metabolic regulation, and defects in this signaling pathway have been implicated in the development of several phenotypes of metabolic syndrome.1 GR signaling depends not only on the circulating cortisol levels but also on the intracellular production of cortisol through reduction of cortisone, the inactive glucocorticoid. The enzymes catalyzing the conversion between cortisone and cortisol are 11β-hydroxysteroid dehydrogenases (11β-HSDs). Among them, the type 1 isoform (11β-HSD-1), highly expressed in liver and adipose tissue, predominantly reduces cortisone to cortisol, and the type 2 isoform (11β-HSD-2), primarily expressed in kidney, oxidizes cortisol to cortisone. A potential role for 11β-HSD-1 inhibitors in metabolic syndrome, type 2 diabetes, and obesity has been established using transgenic mice.2−4 On the basis of these findings, in recent years, 11β-HSD-1 is recognized as a promising target in metabolic disease. 1−4In the past decade, industrial and academic researchers have reported several classes of 11β-HSD-1 inhibitors with varied scaffolds, including sulfonamides (e.g., BVT-14225, 1a), amides (e.g., PF-877423, 2) (Figure 1), triazoles (e.g., Merck 544), and thiazolones (e.g., AMG-221).5−8 In a phase II clinical trial, 11β-HSD-1 inhibitor INCB-13739 (structure undisclosed) significantly improved insulin sensitivity in type 2 diabetes patients who failed on metformin treatment and lowered triglyceride and cholesterol levels of patients with hyperlipidaemia and hypertriglyceridemia.9 Currently, other examples such as PF-915275, MK-0916, and AZD-4071 are being evaluated in phase I/II trials for potential oral treatment of metabolic diseases. 10−12We recently disclosed a new series of sulfonamides (e.g., 1b, Figure 1) with high inhibitory activity against 11β-HSD-1, and compound 1b showed a short duration of action in a pharmacodynamics (PD) model. 13 As part of our continuing

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Thermogenesis and Related Metabolic Targets in Anti-Diabetic Therapy

Arch

2011

Diabetes - Perspectives in Drug Therapy

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Exercise, together with a low-energy diet, is the first-line treatment for type 2 diabetes type 2 diabetes . Exercise improves insulin sensitivity insulin sensitivity by increasing the number or function of muscle mitochondria mitochondria and the capacity for aerobic metabolism, all of which are low in many insulin-resistant subjects. Cannabinoid 1-receptor antagonists and β-adrenoceptor agonists improve insulin sensitivity in humans and promote fat oxidation in rodents independently of reduced food intake. Current drugs for the treatment of diabetes are not, however, noted for their ability to increase fat oxidation, although the thiazolidinediones increase the capacity for fat oxidation in skeletal muscle, whilst paradoxically increasing weight gain.There are a number of targets for anti-diabetic drugs that may improve insulin sensitivity insulin sensitivity by increasing the capacity for fat oxidation. Their mechanisms of action are linked, notably through AMP-activated protein kinase, adiponectin, and the sympathetic nervous system. If ligands for these targets have obvious acute thermogenic activity, it is often because they increase sympathetic activity. This promotes fuel mobilisation, as well as fuel oxidation. When thermogenesis thermogenesis is not obvious, researchers often argue that it has occurred by using the inappropriate device of treating animals for days or weeks until there is weight (mainly fat) loss and then expressing energy expenditure energy expenditure relative to body weight. In reality, thermogenesis may have occurred, but it is too small to detect, and this device distracts us from really appreciating why insulin sensitivity has improved. This is that by increasing fatty acid oxidation fatty acid oxidation more than fatty acid supply, drugs lower the concentrations of fatty acid metabolites that cause insulin resistance. Insulin sensitivity improves long before any anti-obesity effect can be detected.

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Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 in Antidiabetic Therapy

Cited by 22 publications

References 101 publications

Endocrine, Lifestyle, and Genetic Factors in the Development of Metabolic Syndrome

Endocrine, Lifestyle, and Genetic Factors in the Development of Metabolic Syndrome

Discovery of 2-Alkyl-1-arylsulfonylprolinamides as 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Thermogenesis and Related Metabolic Targets in Anti-Diabetic Therapy

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